Genetics of autism

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Behind the Headlines

Friday July 11 2008

The Daily Telegraph today reports of “hopes that a new generation of treatments is about to emerge” for autism. This is based on a new study, which has shown that “autism could be caused by ‘connections’ in the brain failing to form properly”. The study looked at 88 families in the Middle East, Turkey and Pakistan, and has identified six new genes associated with autism.

Autism and the related spectrum of disorders are very complex, and a wide variety of individually rare mutations appear to be involved. This is supported by the fact that in each of the five families in the study, each genetic mutation was in a different region, with different genes affected. Further research will be needed to confirm that the mutations identified in this study are in fact the genetic causes of autism in these families.

However, this study does provide valuable information in the search for the causes of autism, and may help to further understand the biological changes underlying this condition. However, at this stage, the findings do not specifically support any type of therapy, and drug treatments based on these findings are a long way off.

Where did the story come from?

Drs Eric Morrow, Seung-Yun Yoo and colleagues from Harvard Medical School and other hospitals, medical research centres, and universities in the US, Turkey, Saudi Arabia, Kuwait and Pakistan carried out this research. The study was funded by Cure Autism Now, the Nancy Lurie Marks Family Foundation, the Simons Foundation, the Harvard Kuwait Project, the Developmental Disabilities Research Center of Children’s Hospital Boston, the Clinical Investigator Training Program of Harvard and Massachusetts Institute of Technology, Pfizer Inc., Merck & Co., the Anne and Paul Marcus Foundation, the Charles H. Hood Foundation, and the National Institutes of Health. It was published in the peer-reviewed journal Science.

What kind of scientific study was this?

This was a genetic study that aimed to locate regions of the DNA where genes associated with autism might be located. They did this by using a technique called “homozygosity mapping”, which looks at the DNA of families where the affected child has parents who are closely related.

Our DNA is found in our chromosomes, and we have two copies of each of our 23 chromosomes. One copy of each chromosome is inherited from our mother, and one from our father. In turn, we pass on one copy of each chromosome to our offspring. If two people are related, they will share portions of the DNA on their chromosomes because they share a common ancestor. If related parents share a portion of DNA that contains a recessive mutation (a mutation that does not cause a disease unless there are two copies), and the child inherits these shared portions of DNA, they will be affected by the disease. Homozygosity mapping looks for these shared regions of DNA in children with the disease to try to locate the mutations.

The researchers in this study identified 104 families from the Arabic Middle East, Turkey and Pakistan, where one or more of the children had been diagnosed with autism, using standard criteria. In 88 of these families, the parents of the children were first cousins. In each of these families, researchers looked for regions of DNA that were shared between the parents and to see if their affected children had inherited both copies of the shared region. They looked to see whether the shared regions were the same or different in different families. If families all had the same shared regions this would indicate that autism had the same genetic cause in these families.

“At the moment, we understand the genetic causes of 15 to 20 percent of autism. The remaining 80 percent remain unexplained.”

Christopher Walsh, lead author

The researchers also looked at the shared regions to see if they could identify genes and mutations within these regions that might be causing autism. They then looked to see if other unrelated people with autism had the same mutations, and whether they could find the mutations in people who didn’t have autism. The researchers also looked at the genes that were affected by these mutations, to see if they were active in the brain.

What were the results of the study?

The researchers found that different regions of the DNA were associated with autism in different families – suggesting that different genes were playing a role. In some of these regions, the researchers found that there were pieces of missing DNA called deletions. They found deletions in five out of the 88 families with related parents.

One family had a deletion on chromosome 3, This mutation was absent in 393 unrelated children with autism, 92 people without autism, and in 2,200 samples from the Autism Genetic Resource Exchange. This deletion removes a gene of unknown function called c3orf58, and lies near a gene called NHE9, which is known to be disrupted in a family with a neuropsychiatric disorder and mild mental retardation.

A number of other deletions were found in individual families, and these deletions were near to various genes (PCDH19, CNTN3, RNF8, SCN7A) all of which are highly active in the brain. NHE9, c3orf58 and PCDH19 are known to be switched on when nerve cells are activated. PCDH19 is also known to be involved in brain development.

What interpretations did the researchers draw from these results?

The researchers concluded that their findings confirm the genetic complexity of autism, but that homozygosity mapping is a useful tool in helping to unravel this complexity. They say that their data supports the existence of many genetic changes associated with autism, which are themselves individually rare. They suggest that the disruption of different genes that play a role in autism may lead to a disruption in the development of connections between nerve cells (synapses) in the brain.

What does the NHS Knowledge Service make of this study?

This was a well-conducted genetic study that shows the importance of the homozygosity mapping technique for investigating complex diseases such as the autistic spectrum disorders. As the authors point out, the way in which different individuals are affected by autistic spectrum disorders varies widely and, correspondingly, there are a variety of different genes involved in these differing forms. This makes identification of genes involved in autistic spectrum disorders difficult. It also means that the mutations identified in this study may not play a role in the development of autistic spectrum disorders in most other groups of people. This is supported by the fact that each of the mutations identified only occurred in one family.

Although this study did identify genetic mutations that were inherited in a way that was consistent with them potentially being a cause of autism in these families, further data will be needed to confirm that they are indeed the causative mutations. For example, research will be needed to find out whether the deletions can affect the switching on and off of the genes near to the deleted regions, and that these changes can affect brain development. This study provides valuable information in the search for the causes of autism, and may help us to further understand the biological changes underlying this condition. However, treatments based on these findings are a long way off.